www.nature.com/scientificreports OPEN Progressive patterns of neurological disability in multiple sclerosis and neuromyelitis optica spectrum disorders Tetsuya Akaishi1,2*, Toshiyuki Takahashi1,3, Tatsuro Misu1, Michiaki Abe2, Tadashi Ishii2, Juichi Fujimori4, Masashi Aoki1, Kazuo Fujihara5 & Ichiro Nakashima4 The progressive patterns of neurological disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) and the signifcance of clinical relapses to the progressions of neurological disability in these diseases have not been fully elucidated. In this study, to elucidate the impact of relapses to the progression of accumulated neurological disability and to identify the factors to afect the progression of neurological disability in MS and NMOSD, we followed 62 consecutive MS patients and 33 consecutive NMOSD patients for more than 5 years with the clinical symptoms, relapse occurrence, and Expanded Disability Status Scale (EDSS) in the chronic phase. All enrolled MS patients were confrmed to be negative for serum anti-myelin oligodendrocyte glycoprotein antibody. As a result, patients with NMOSD showed signifcantly severer neurological disability at 5 years from onset than MS patients. Progression in EDSS score was almost exclusively seen after clinical attacks in NMOSD, whereas progression could be observed apart from relapses in MS. Neurological disability did not change without attacks in NMOSD, whereas it sometimes spontaneously improved or deteriorated apart from relapses in MS (p < 0.001). In patients with MS, those with responsible lesions primarily in spinal cord were more likely to show such spontaneous improvement. In conclusion, clinical deterioration in NMOSD patients is irreversible and almost exclusively takes place at the timing of clinical attacks with stepwise accumulation of neurological disability. Meanwhile, changes in EDSS score can be seen apart from relapses in MS patients. Neurological disability in MS patients is partly reversible, and the patients with disease modifying drugs sometimes present spontaneous improvement of the neurological disability. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are major autoimmune-related neurological diseases that predominantly impairs the central nervous system (CNS) but have distinct patho- physiological mechanisms1,2. Both diseases typically present recurrent clinical attacks with lesions in cerebrum, optic nerves, brainstem, and spinal cord 1,3. At present, MS is diagnosed based on the dissemination of lesions in time and space4–6, whereas NMOSD is diagnosed both by the clinical history and the presence of serum anti- aquaporin-4 antibody (AQP4-IgG)1,7. Te accumulation of neurological impairment in MS is thought to be mainly comprised of the following two components: subclinical progressive brain atrophy and recurrent clinical relapses during which the responsible lesions are contrast-enhanced in MRI 8. Based on this concept, clinical course of MS is generally categorized into the following three subtypes: primary progressive MS (PPMS), relapsing–remitting MS (RRMS), and secondary progressive MS (SPMS)9,10. Meanwhile, progressive pattern of neurological impairment in NMOSD has not been so much studied until now, although the subsequent neurological disability is generally severer in NMOSD than 1Department of Neurology, Tohoku University Graduate School of Medicine, Seiryo-machi 1-1, Aoba-ku, Sendai, Miyagi 980-8574, Japan. 2Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan. 3Department of Neurology, National Hospital Organization Yonezawa National Hospital, Yonezawa, Japan. 4Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan. 5Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan. *email: [email protected] SCIENTIFIC REPORTS | (2020) 10:13890 | https://doi.org/10.1038/s41598-020-70919-w 1 Vol.:(0123456789) www.nature.com/scientificreports/ in MS11–13. From before, the progression of neurological disability in NMOSD has been empirically thought to occur mainly at the timing of clinical attacks 14, but whether it occurs even during the intermittent period between attacks or not has not been proved yet. Because the expected clinical course will surely afect the achieved out- comes in clinical studies enrolling the patients with these diseases, elucidating the characteristic clinical course and factors that afect the progression of neurological disability in these diseases has many clinical signifcances. In this study, we enrolled an enough number of MS and NMOSD patients who have their clinical onset between 2000 and 2015, and followed their neurological disability every year from the frst visit to our hospital. Te progressive pattern of their neurological disability was evaluated with other information such as patient background and relapses to identify the clinical factors that mainly regulate the progression of neurological disability in each of MS and NMOSD. Methods Patients. For this study, a total of 62 consecutive MS patients and 33 consecutive AQP4-IgG-positive NMOSD patients, who had their clinical onset between 2000 and 2015 and treated in our university hospi- tal were initially collected. Tese initial cohorts were prospectively followed up, among which 57 MS patients (91.9%) and 31 NMOSD patients (93.9%) were followed and treated in our university hospital for more than 5 years from their onset. All enrolled MS patients were confrmed to be negative for the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody by utilizing the cell-based assay method15. Te pres- ence of serum AQP4-IgG in the enrolled NMOSD patients was also confrmed based on the cell-based assay method16,17. All of the 5 MS patients who was not followed for more than 5 years dropped out because of moving. One of the 2 NMOSD patients who was not followed for more than 5 years died because of a malignant tumor 2 years afer the onset of NMOSD, but another patient dropped out because of moving. Collected data. In these patients, comprehensive clinical information was collected, such as onset age, sex, follow up period as of 2019, types of relapse preventive therapies, type and timing of clinical attacks, and the titer of serum anti-AQP4 antibody. Te irreversible neurological impairment was evaluated with the Expanded Disability Status Scale (EDSS) in every 1 or 2 years in these patients18. Because neurological disability can drasti- cally exacerbate and recover in the acute and subacute phases of clinical relapses with proper treatments with immune-suppressants, EDSS scores within 3 months from the last relapse were not used in this study. Relapses in MS and NMOSD were defned by the presence of clinically evidenced gadolinium-enhanced T1-weighted lesions with the neurological symptoms sustained for more than 24 h in the absence of fever or infection 4. As for other clinical information, data about the number of cerebral lesions at 5 years from the onset and the site of lesion responsible for the neurological disability (i.e. cerebral, optic nerves, brainstem, spinal cord) were also collected in MS patients. To identify the factors that afect the neurological disability in MS, we also evaluated the gray matter volume and white matter lesion volume in some of them with a volumetric method as previously reported19. Statistical analysis. Comparisons of two distributions were performed with either of the Student’s t-test or Mann–Whitney U test, based on the normality of distributions. Comparisons of frequencies were performed with either of the chi-squared test or Fisher’s exact test, based on the size in each cell. A value of p < 0.05 was regarded to be statistically signifcant. Te analyses were conducted using either SPSS Statistics Base 22 sofware (IBM, Armonk, NY, USA) or MATLAB R2015a (MathWorks, Natick, MA, USA). Ethical approval. Tis study was approved by the institutional review board of the Tohoku University Graduate School of Medicine (approval number: 2010589), and was carried out in accordance with the standards stated in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent. Informed consent was obtained from all individual participants included in the study. Results Cohort demographics. Te total follow-up period with EDSS evaluation in the initially collected MS patients with onset between 2000 and 2015 was 337 person-year (62 patients) as of Oct 2019; that in the initially collected NMOSD patients with onset between 2000 and 2015 was 229 person-year (33 patients). Patients’ back- ground in both groups are listed in Table 1 and compared between the groups. As for therapeutic interventions, in MS group, 58 of the 62 patients have been treated with disease modifying drugs (DMDs), such as interferon (IFN) beta, glatiramer acetate, fngolimod, or natalizumab. In the 58 patients with DMDs, 26 were initially treated with IFN beta, but later changed DMD to fngolimod. Other 2 patients have been treated with oral prednisolone (PSL) and the remaining 2 patients are untreated. In NMOSD group, 32 of the 33 patients were treated with low-dose oral PSL (< 20 mg/day) with or without other immune-suppressants (i.e. azathioprine, cyclosporine, tacrolimus). Te remaining 1 NMOSD patient has not been treated with any kind of relapse pre- ventive therapies. Progression of neurological disability in total. Te progressions of EDSS in